Amino pyrimidine SSAO inhibitors

ABSTRACT

The present invention provides compounds of the Formula (I), or a pharmaceutically acceptable salt thereof, where n and R1 are defined herein, methods of treating patients for liver disease, and processes for preparing the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/011,855, filed Jun. 19, 2018, which is a continuation ofInternational Application No. PCT/CN2017/095999, filed Aug. 4, 2017,which claims priority benefit of International Application No.PCT/CN2016/094833, filed Aug. 12, 2016, the disclosures of each of whichare incorporated herein by reference.

This invention relates to amino pyrimidine compounds, pharmaceuticallyacceptable salts of the compounds, and therapeutic uses of the compoundand salts.

Semicarbazide-sensitive amino oxidase/vascular adhesion protein-1(SSAO)/VAP-1) is a member of the semicarbazide-sensitive amino oxidasefamily. SSAO/VAP-1 has been alternatively referred to as VAP-1 or SSAO.SSAO/VAP-1 is an enzyme that exists both as a membrane-bound and asoluble isoform; it is predominantly expressed from endothelial cellsurface, vascular smooth muscle and adipose cells. SSAO/VAP-1participates in many cellular processes including glucose disposition,inflammation responses, and leukocyte recruitment. High activity levelsof this enzyme are associated with diabetes, atherosclerosis, strokes,chronic kidney disease, and Alzheimer's disease, among other disorders.Recently SSAO/VAP-1 has been implicated in the pathogenesis of liverdiseases such as fatty liver disease. Weston, C. J. et al., J Neural.Transm. 2011, 118, 1055-1064. Fatty liver disease (FLD) encompasses aspectrum of disease states where fat accumulates in the liver inexcessive amounts and is accompanied by inflammation. FLD can lead tonon-alcoholic fatty liver disease (NAFLD), which is characterized byinsulin resistance. Unchecked NAFLD progresses to a persistentinflammatory response or non-alcoholic steatohepatitis (NASH),progressive liver fibrosis, and eventually to cirrhosis. Currently thereis a need to provide alternative treatment therapies for liver diseasessuch as NAFLD and/or NASH.

It is thought that a SSAO/VAP-1 inhibitor will reduce liver inflammationand fibrosis and thereby provide a treatment for liver diseases, inparticular, a treatment for NAFLD and/or NASH. The present inventionprovides compounds that inhibit the SSAO/VAP-1 enzyme and which mayaddress one or more of the needs.

The present invention provides compounds of Formula 1:

where n is 1 or 2; and R1 is H or —CH₃; or a pharmaceutically acceptablesalt thereof. The bond to fluorine, which is illustrated as

, indicates that the fluorine atom and the methoxypyrimidine group canbe either Z (zusammen, together) or E (entgegen, opposite) relative toeach other (Brecher, J., et al., “Graphical Representation ofStereochemical Configuration”, Pure and Appl. Chem, 2006, 78(10) 1897,at 1959). The structure illustrated by Formula 1 includes compounds withthe Z stereochemical configuration, the E stereochemical configuration,or a mixture of compounds in the Z or E stereochemical configurations.Preferred compounds of the invention have the E stereochemicalconfiguration.

In one form, the present invention provides compounds of Formula 1 as afree base. In other form, the present invention provides compounds ofFormula 1 as acid addition salts, such as a mono or di HCl additionsalt(s) or a sulfonate salt, preferable a 4-methylbenzenesulfonate (atoslyate salt).

In one form, the present invention provides a compound of Formula 2:

where n is 1 or 2; and R1 is H or —CH₃; or a pharmaceutically acceptablesalt thereof.

In another form, the present the present invention provides a compoundof Formula 3:

where n is 1 or 2; and R1 is H or —CH₃; or a pharmaceutically acceptablesalt thereof.

In one embodiment, the present invention provides a compound accordingto one of Formulae 1, 2, and 3 where n is 1, or a pharmaceuticallyacceptable salt thereof. In another embodiment, the present inventionprovides a compound according to one of Formulae 1, 2, and 3 where n is2, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compoundaccording to one of Formulae 1, 2, and 3 where R1 is H, or apharmaceutically acceptable salt thereof. In yet another embodiment, thepresent invention provides a compound according to one of Formulae 1, 2,and 3 where R1 is —CH₃, or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a compound of Formula 4

where R1 is H or —CH₃, or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a compound according toof Formula 5

or a pharmaceutically acceptable salt thereof. In one embodiment, thecompound of Formula 5 is provided as an acid addition salt. Preferablythe acid addition salt is a mono or di HCl addition salt or a sulfonatesalt, such as a methylsulfonic acid or 4-methylbenzenesulfonic acidaddition salt to provide a mesylate salt or a 4-methylbenzenesulfonate(tosylate) salt.

In another form, the present invention provides a pharmaceuticalcomposition comprising a compound according to any one of Formulae 1 to5, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient. In one embodiment, thepharmaceutical composition comprises a compound according to Formula 5,or a pharmaceutically acceptable salt thereof. Preferably thepharmaceutically acceptable anion(s) for the salt is a mono or dichloride, mesylate or a 4-methylbenzenesulfonate (tosylate).

In another form, the present invention provides a method of treating apatient in need of treatment for liver disorder. The method comprisesadministering to the patient an effective amount of a pharmaceuticalcomposition that comprises a compound according to any of Formulae 1 to5, or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a method of treating apatient in need of treatment for a liver disorder. The method comprisesadministering to the patient an effective amount of a compound accordingto any one of Formulae 1 to 5, or a pharmaceutically acceptable saltthereof. Examples of liver disorders include liver inflammation,fibrosis, and steatohepatitis. In certain embodiments, the methodcomprises treating a patient in need of treatment for a liver disorderwhere the liver disorder is selected from: liver fibrosis, alcoholinduced fibrosis, alcoholic steatosis, non-alcoholic fatty liver disease(NAFLD), and non-alcoholic steatohepatitis (NASH). In a particularlypreferred embodiment, the method comprises treating a patient in need oftreatment for non-alcoholic steatohepatitis (NASH).

In another form, the present invention provides a compound of Formula 6,which is a(2E)-3-Fluoro-2-({[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]oxy}methyl)prop-2-en-1-amine4-methylbenzenesulfonate (1:1) salt.

In one embodiment, the(2E)-3-Fluoro-2-({[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]oxy}methyl)prop-2-en-1-amine4-methylbenzenesulfonate (1:1) salt is provided in crystalline formcharacterized by an X-ray powder diffraction pattern obtained from aCuKα source (λ=1.54056 Å), which comprises peaks at: a) 18.6, 19.1,21.0, 21.9, and 22.4+/−0.2° in 2 theta, orb) 17.6, 11.0, 16.8, 18.6,19.1, 21.0, 21.9, 22.4 and 26.1+/−0.2° in 2 theta.

In another form, the present invention provides a compound according toany one of Formulae 1 to 6, or a pharmaceutically acceptable saltthereof, for use in therapy. In preferred embodiments, the therapy isfor a liver disorder. Preferably, the therapy is for a liver disorderselected from: liver fibrosis, alcohol induced fibrosis, alcoholicsteatosis, non-alcoholic fatty liver disease, and non-alcoholicsteatohepatitis. In one embodiment, the therapy is for the treatment ofliver fibrosis. In another embodiment, the therapy is for non-alcoholicfatty liver disease. In still yet another embodiment, the therapy is fornon-alcoholic steatohepatitis.

In another form, the present invention provides a compound according toany one of Formulae 1 to 6, or a pharmaceutically acceptable saltthereof, for use in the treatment of a liver disorder. In oneembodiment, the liver disorder is selected from: liver fibrosis, alcoholinduced fibrosis, alcoholic steatosis, non-alcoholic fatty liverdisease, and non-alcoholic steatohepatitis. In another embodiment, theliver disorder is non-alcoholic fatty liver disease or non-alcoholicsteatohepatitis. In a particularly preferred embodiment, the liverdisorder is non-alcoholic steatohepatitis (NASH).

In yet another embodiment, the present invention provides for the use ofa compound according to any one of Formulae 1 to 6 in the manufacture ofa medicament to treat a liver disorder. In preferred embodiments, theliver disorder is selected from: liver fibrosis, alcohol inducedfibrosis, alcoholic steatosis, non-alcoholic fatty liver disease, andnon-alcoholic steatohepatitis.

The term “pharmaceutically-acceptable salt” as used herein refers a saltof a compound of the invention considered to be acceptable for clinicaland/or veterinary use. Examples of pharmaceutically acceptable salts andcommon methodology for preparing them can be found in “Handbook ofPharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al.,2nd Revised Edition, Wiley-VCH, 2011 and S. M. Berge, et al.,“Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66(1),1-19.

The pharmaceutical compositions for the present invention may beprepared using pharmaceutically acceptable additives. The term“pharmaceutically acceptable additive(s)” as used herein for thepharmaceutical compositions, refers to one or more carriers, diluents,and excipients that are compatible with the other additives of thecompositions or formulations and not deleterious to the patient.Examples of pharmaceutical compositions and processes for theirpreparation can be found in “Remington: The Science and Practice ofPharmacy”, Loyd, V., et al. Eds., 22^(nd) Ed., Mack Publishing Co.,2012. Non-limiting examples of pharmaceutically acceptable carriers,diluents, and excipients include the following: saline, water, starch,sugars, mannitol, and silica derivatives; binding agents such ascarboxymethyl cellulose and other cellulose derivatives, alginates,gelatin, and polyvinyl-pyrrolidone; kaolin and bentonite; polyethylglycols.

As used herein, the term “effective amount” refers to an amount that isa dosage, which is effective in treating a disorder, such as a liverdisease including liver inflammation, fibrosis, and steatohepatitis. Theattending physician, as one skilled in the art, can readily determine aneffective amount by the use of conventional techniques and by observingresults obtained under analogous circumstances. In determining aneffective amount or dose of a compound, a number of factors areconsidered, including, but not limited whether the compound or its salt,will be administered; the co-administration of other agents, if used;the species of mammal; its size, age, and general health; the degree ofinvolvement or the severity of the disorder; the response of theindividual patient; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of other concomitant medication; and other relevantcircumstances.

As used herein, the terms “treating”, “to treat”, or “treatment”,includes slowing, reducing, or reversing the progression or severity ofan existing symptom, disorder, condition, or disease, which can includetreating liver disease, such as, liver inflammation, fibrosis, andsteatohepatitis.

As used herein, the term “patient” refers to a mammal, fowl, or fish.Preferably, the patient is a human or companion mammal, such as, a dogor cat or other domesticated mammal, such as, a cow, pig, horse, sheep,rabbit, and goat.

A treating physician, veterinarian, or other medical person will be ableto determine an effective amount of the compound for treatment of apatient in need. Preferred pharmaceutical compositions can be formulatedas a tablet or capsule for oral administration, a solution for oraladministration, or an injectable solution. The tablet, capsule, orsolution can include a compound of the present invention in an amounteffective for treating a patient in need of treatment.

The abbreviations used herein are defined according to Daub G. H., etal., “The Use of Acronyms in Organic Chemistry” Aldrichimica Acta, 1984,17(1), 6-23. Other abbreviations are defined as follows: “ACN” refers toacetonitrile; “AUC” refers to area under the curve; “Boc” representstert-butoxycarbonyl; “DCM” refers to dichloromethane; “DIPEA” refers toN,N-diisopropylethylamine; “DMF” refers to dimethylformamide; “DMSO”refers to dimethylsulfoxide; “EDTA” refers to ethylenediaminetetraaceticacid; “EGTA” refers to ethylene glycol tetraacetic acid; “ES/MS” refersto electrospray mass spectroscopy; “EtOAc” refers to ethyl acetate;“HEPES” refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid;“HPLC” refers to high performance liquid chromatography; “hr or hrs”refers to hour or hours; “HRP” refers to horse radish peroxidase; “IC₅₀”refers to the concentration of an agent which produces 50% of themaximal inhibitory response possible for that agent (relative IC₅₀), orthe concentration of an agent which produces 50% inhibition of thetarget activity compared to placebo control (absolute IC₅₀); “MAOa andMAOb” refers to monoamine oxidas a and b isoform, respectively; “MeOH”refers to methyl alcohol or methanol; “min” refers to minutes; “MS”refers to mass spectroscopy; “PE” refers to petroleum ether; “R_(t)”refers to retention time; “SSAO” refers to semicarbazide-sensitive amineoxidase; and “hSSAO” refers to human SSAO.

The compounds of the present invention, or salts thereof, may beprepared by a variety of procedures, some of which are illustrated inthe Preparations, and the Examples below. The product(s) of each step inthe procedures below can be recovered by conventional methods includingextraction, evaporation, precipitation, chromatography, filtration,trituration, and crystallization. Unless noted to the contrary, thereagents and starting materials are readily available.

In the preparations described herein the hydroxyl and aminofunctionalities can be protected to facilitate the synthesis of thecompounds described herein. Examples of protecting functionalities canbe found in “Greene's Protective Groups in Organic Synthesis,” Wuts, P.G. M., et al., Eds. 5th Ed., John Wiley and Sons, 2014. Other functionalgroups that can be readily converted to the hydroxyl group or the aminogroup can be used. Such functional groups, preparations, andtransformations of these groups can be found in “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations” by Larock. R.C., Wiley VCH, 1999 and in “March's Advanced Organic Chemistry:Reactions, Mechanisms and Structure,” Smith, M. B., Ed., 7th Ed.,Wiley-Interscience, 2013.

Chemical Synthesis Section

The following Preparations and Examples further illustrate the inventionand represent typical synthesis of the compounds of the invention.

Preparation 1 tert-Butyl (3S)-3-methoxypyrrolidine-1-carboxylate

Add iodomethane (0.398 g, 2.80 mmol) to a mixture of tert-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate (0.500 g, 2.67 mmol) and sodiumhydride (60 mass % in mineral oil) (0.160 g, 4.01 mmol) in DMF (5 mL).Stir the resulting mixture at room temperature for 2 hours. Quench thereaction with saturated aqueous NH₄Cl aq. (30 mL) and extract with EtOAc(3×30 mL). Discard the aqueous layer. Combine the organic extracts andwash with brine, dry over Na₂SO₄, filter, and evaporate the filtrate todryness to give the title compound (475 mg, 0.475 g, 88.4%). The crudematerial can be used in the next step without further purification.ES/MS (m/z): 224.2 (M+Na).

Preparation 2 (3 S)-3-Methoxypyrrolidine

Stir a solution of tert-butyl (3S)-3-methoxypyrrolidine-1-carboxylate(475 mg, 2.36 mmol) and trifluoroacetic acid (1 mL, 13.23 mmol) in DCM(3 mL) at room temperature for 1 hour. Concentrate the reaction mixtureunder vacuum to give the title compound (240 mg, 2.35 mmol, 99.5%),which can be used in the next step without further purification.

Preparation 3 1-(5-Benzyloxypyrimidin-2-yl)piperidin-4-ol

Stir a mixture of 5-benzyloxy-2-chloro-pyrimidine (2.30 g, 9.90 mmol),piperidin-4-ol (1.23 g, 11.9 mmol) and DIPEA (3.88 mL, 29.7 mmol) in DMF(30 mL, 388 mmol) at 100° C. under a N₂ atmosphere for 17 hrs. Dilutethe mixture with water (200 mL) and extract with EtOAc (3×50 mL).Combine the organic extracts; wash with brine (3×50 mL), dry overNa₂SO₄, filter, and concentrate the filtrate. Subject the residue tosilica gel flash column chromatography eluting with a mixture of 60%EtOAc and 40% PE to give the title compound (2.00 g, 6.31 mmol, 63.7%)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.40-1.60 (m, 2H), 1.90-1.99(m, 2H), 3.17-3.29 (m, 2H), 3.85-3.95 (m, 1H), 4.25-4.39 (m, 2H), 5.09(s, 2H), 7.38-7.52 (m, 5H), 8.14 (s, 2H).

Preparation 4 2-(4-Hydroxy-1-piperidyl)pyrimidin-5-ol

Add palladium (10 mass % on carbon, 600 mg, 0.564 mmol) to1-(5-benzyloxypyrimidin-2-yl)piperidin-4-ol (2.00 g, 6.31 mmol) in MeOH(40 mL, 989 mmol). Stir the resulting mixture at 15° C. under a hydrogenatmosphere (103 kPa) for 2 hrs. Filter the resulting mixture throughdiatomaceous earth. Concentrate the filtrate to give the title compound(0.70 g, 3.59 mmol, 56.8%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ1.23-1.38 (m, 2H), 1.60-1.77 (m, 2H), 2.65-2.90 (m, 2H), 3.00-3.25 (m,2H), 3.50-3.70 (m, 2H), 4.05-4.16 (m, 1H), 7.90 (s, 2H).

Preparation 5 tert-ButylN-[(E)-2-[(2-chloropyrimidin-5-yl)oxymethyl]-3-fluoro-allyl]carbamate

Add K₂CO₃ (5.71 g, 41.3 mmol) to a solution of 2-chloropyrimidin-5-ol(5.01 g, 38.3 mmol) and tert-butylN-[(E)-2-(bromomethyl)-3-fluoro-allyl]carbamate (3.67 g, 13.7 mmol) inDMF (25 mL). Stir the resulting solution at room temperature for 12hours. Quench the reaction by adding water (80 mL) and EtOAc (100 mL).Separate the organic and aqueous phases. Extract the aqueous phase withEtOAc (3×100 mL). Combine all the organic extracts. Dry the combinedorganic extracts over Na₂SO₄, filter, and concentrate the filtrate undervacuum to provide a residue. Subject the residue to silicia gel flashchromatography eluting with a mixture of 30% EtOAc in hexanes to givethe title compound as a white solid (4.15 g, 13.1 mmol, 96% yield).ES/MS (m/z): 340 (M+Na).

Preparation 6 tert-ButylN—[(Z)-3-fluoro-2-[[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]allyl]carbamate

Stir a mixture of 2-(4-hydroxy-1-piperidyl)pyrimidin-5-ol (400 mg, 2.05mmol), tert-butyl N—[(Z)-2-(bromomethyl)-3-fluoro-allyl]carbamate (1.10g, 4.02 mmol) and K₂CO₃ (0.858 g, 6.15 mmol) in DMF (10 mL) at 60° C.for 3 hrs. Dilute the resulting mixture with EtOAc (50 mL). Sequentiallywash the mixture with water (100 mL) then brine (2×50 mL). Dry theorganic phase over Na₂SO₄, filter, and concentrate the filtrate toprovide a residue. Subject the residue to silica gel flash columnchromatography eluting with a gradient of 65-75% EtOAc in PE to give thetitle compound (558 mg, 1.46 mmol, 71.2%) as a yellow gum. ¹H NMR (400 MHz, CDCl₃) δ 1.25 (s, 9H), 1.40-1.65 (m, 4H), 1.89-1.98 (m, 2H),3.23-3.30 (m, 2H), 3.91 (s, 1H), 3.89-3.97 (m, 1H), 4.36-4.40 (m, 2H),4.64 (s, 2H), 4.76 (br, 1H), 6.62 (d, J=84.0 Hz, 1H) 8.10 (s, 2H).

Preparation 7 tert-ButylN-[(E)-3-F-2-[[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]allyl]carbamate

Combine tert-butylN-[(E)-2-[(2-chloropyrimidin-5-yl)oxymethyl]-3-fluoro-allyl]carbamate(21.3 g, 67.0 mmol), piperidin-4-ol (25.0 g, 235 mmol), and DIPEA (41mL, 235 mmol) in 1,4-dioxane (200 mL). Heat the resulting mixture to105° C. under a N₂ atmosphere for 7 hours. Concentrate the mixture andpartition it between water (100 mL) and EtOAc (150 mL), then separatethe phases. Extract the aqueous phase with EtOAc (100 mL). Combine allthe organic phases. Wash with brine (100 mL), dry over Na₂SO₄, filter,and concentrate the filtrate to provide a residue. Dissolve the residuein EtOAc (21 mL), and then drop-wise add heptane (126 mL). Stir theresulting mixture at room temperature for 20 hours. Filter the mixtureto collect the solid, rinse the solid with EtOAc/heptane (5:1, 21 mL).Dry the solid under vacuum to give the title compound (23.5 g, 61.5mmol, 91.7%). ES/MS (m/z): 383 (M+H).

Preparation 8 tert-ButylN-[(E)-3-fluoro-2-[[2-(4-methoxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]allyl]carbamate

Divide tert-butylN-[(E)-2-[(2-chloropyrimidin-5-yl)oxymethyl]-3-fluoro-allyl]carbamate(4.10 g, 12.9 mmol) into 2 equal parts (2.05 g+2.05 g) and place eachpart into a separate microwave vial (20 mL). Into each vial, add4-methoxypiperidine (4.31 g, 37.3 mmol), 1,4-dioxane (30 mL, 15 mL) andDIPEA (6 mL, 34.4 mmol, 3 mL). Flush the vials with N₂ gas, seal, andheat to 120° C. for 12 hours by microwave. Combine the two reactionmixtures and concentrate under vacuum to provide a residue. Subject theresidue silica gel flash chromatography eluting with a mixture of 30%EtOAc in hexanes to give the title compound as a yellow oil (4.24 g,10.2 mmol, 79%). ES/MS (m/z): 397 (M+H).

Preparation 9 tert-ButylN-[(E)-3-fluoro-2-[[2-[(3S)-3-methoxypyrrolidin-1-yl]pyrimidin-5-yl]oxymethyl]allyl]carbamate

Add tert-butylN-[(E)-2-[(2-chloropyrimidin-5-yl)oxymethyl]-3-fluoro-allyl]carbamate(400 mg, 1.26 mmol) to a mixture of (3S)-3-methoxypyrrolidine (240 mg,2.37 mmol) and K₂CO₃ (0.696 g, 5.04 mmol) in 1,4-dioxane (5 mL). Stirthe resulting mixture at 120° C. under microwave conditions for 12hours. Concentrate the mixture under vacuum to provide the titlecompound as a crude material, which can be used in the next step withoutfurther purification (481 mg, 1.26 mmol, 99.9%). ES/MS (m/z): 383.2(M+H).

Preparation 10 tert-ButylN-[(E)-3-fluoro-2-[[2-[(3S)-3-hydroxypyrrolidin-1-yl]pyrimidin-5-yl]oxymethyl]allyl]carbamate

Dissolve tert-butylN-[(E)-2-[(2-chloropyrimidin-5-yl)oxymethyl]-3-fluoro-allyl]carbamate(594.3 mg, 1.87 mmol) and (3S)-pyrrolidin-3-ol (488.9 mg, 5.61 mmol) in1,4-dioxane (15 mL) and DIPEA (3 mL, 17.2 mmol). Flush the solution withN₂ gas, seal the vessel, and heat the mixture to 120° C. for 12 hours bymicrowave. Concentrate the resulting mixture under vacuum to provide aresidue. Subject the residue to silica gel flash chromatography elutingwith a gradient of 80-90% EtOAc in hexanes to give the title compound asa yellow foam (608.8 mg, 1.57 mmol, 84%). ES/MS (m/z): 369 (M+H).

EXAMPLE 11-[5-[(Z)-2-(Aminomethyl)-3-fluoro-allyloxy]pyrimidin-2-yl]piperidin-4-olhydrochloride

Add tert-butylN—[(Z)-3-fluoro-2-[[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]allyl]carbamate(558 mg, 1.46 mmol) to HCl (4 mol/L) and MeOH (10 mL). Stir theresulting mixture for 1.5 hrs at 10° C. Concentrate the mixture underreduced pressure to provide a residue. Subject the residue to prep-HPLCcolumn: (Phenomenex Synergi C18 150 30 mm, 4 μm) eluting with a gradientof 10 to 15% 0.05% aqueous HCl in ACN; flow rate: 25 mL/min, R_(t): 5.95min to give the title compound with a Z:E ratio of greater than 20:1(456 mg, 1.43 mmol, 98.0%) as a yellow solid. ES/MS (m/z): 283.1 (M+H),¹H NMR (400 MHz, d₄-MeOD) δ 1.56-1.78 (m, 2H), 1.92-2.13 (m, 2H),3.61-3.72 (m, 2H), 3.75 (s, 2H), 3.95-4.06 (m, 1H), 4.11-4.25 (m, 2H),4.89-4.93 (m, 2H), 7.19 (d, J=80.4 Hz, 1H), 8.47 (s, 2H).

EXAMPLE 21-[5-[(E)-2-(Aminomethyl)-3-fluoro-allyloxy]pyrimidin-2-yl]piperidin-4-oldihydrochloride

Combine tert-butylN-[(E)-3-fluoro-2-[[2-(4-hydroxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]allyl]carbamate(31 g, 81.07 mmol), MeOH (20 mL, 494 mmol), and HCl in MeOH (120 mL, 4mol/L, 486.4 mmol). Stir the resulting mixture for 30 hours under a N₂atmosphere at room temperature. Add EtOAc (250 mL) drop-wise and stirthe mixture for 30 minutes. Filter the mixture to collect the solid,rinse the solid with EtOAc (20 mL), and the dry the solid under vacuumto give the title compound with an E:Z ratio of greater than 20:1 (26.4g, 72.8 mmol, 89.8%). ES/MS (m/z): 283 (M+H), ¹H NMR (500 MHz, d₆-DMSO)δ 1.28-1.36 (m, 2H), 1.73-1.76 (m, 2H), 3.18-3.25 (m, 2H), 3.55-3.60 (m,2H), 3.68-3.75 (m, 1H), 4.18 (dt, J=13.5, 4.5 Hz, 2H), 4.65 (d, J=3.0Hz, 2H), 6.55-7.10 (br, 2H), 7.27 (d, J=82.0 Hz, 1H), 8.27 (s, 2H),8.32-8.45 (br, 3H), ¹⁹F NMR (500 MHz, d₆-DMSO) δ 122.2 (s).

EXAMPLE 3(E)-3-Fluoro-2-[[2-(4-methoxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]prop-2-en-1-amine,Dihydrochloride

Dissolve tert-butylN-[(E)-3-fluoro-2-[[2-(4-methoxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]allyl]carbamate(4.2374 g, 10.69 mmol) in HCl in MeOH (100 mL, 50 mmol, 0.5 mol/L). Heatthe resulting clear solution to 60° C. for 4 hours. Concentrate themixture under vacuum to provide a residue (3.95 g). Suspend the residuein MeOH (7 mL) and reflux the mixture to provide a clear solution. Coolthe solution to room temperature to give needle crystals, and then coolthe mixture to −20° C. Filter the mixture to collect the solid, wash thesolid with cool MeOH to give the title compound as light yellow crystals(2.73 g, 7.01 mmol, 66%). The resulting yellow crystals can be furtherpurified via recrystallization with the same procedure described aboveto give the title compound as colorless, crystalline material with anE:Z ratio of greater than 20:1 ES/MS (m/z): 297 (M+H), ¹H NMR (500 MHz,d₆-DMSO) δ 1.33-1.40 (m, 2H), 1.84-1.89 (m, 2H), 3.26 (dt, J=13.5, 9.5Hz, 2H), 3.27 (s, 3H), 3.40-3.45 (m, 1H), 3.56-3.62 (m, 2H), 4.11 (dt,J=13.5, 5.0 Hz, 2H), 4.62 (d, J=3.0 Hz, 2H), 5.26-5.94 (br, 1H), 7.27(d, J=82.0 Hz, 1H), 8.26 (s, 2H), 8.21-8.31 (br, 3H), ¹⁹F NMR (500 MHz,d₆-DMSO) δ 122.1 (s).

EXAMPLE 4(E)-3-fluoro-2-[[2-(4-methoxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]prop-2-en-1-amine

DissolveN-[(E)-3-Fluoro-2-[[2-(4-methoxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]allyl]carbamate (167.0 mg, 0.42 mmol) in 0.95M HCl solution in 18 mLEtOAc/MeOH (10:1 v/v). Stir the mixture overnight. Concentrate theresulting suspension under vacuum and dissolve the residue in water.Subject the residue to pre-HPLC; LC column: XBridge® C18 30×150 mm 5 μm;eluting with a gradient of 14 to 24% 10 mM NH₄HCO₃ aqueous solution inACN from 0-11 minutes; column temperature: room temperature; flow rate:35 mL/min, R_(t)=7.8 minutes stopping after 17 min. monitor by UV.Collect and concentrate the appropriate fractions to provide a residueas an oil. The residue is dissolved in water and lyophilized to give thetitle compound as a white solid with an E:Z ratio greater than 20:1 (97mg, 0.31 mmol, 74%, 95% purity). ES/MS (m/z): 297 (M+H), ¹H NMR (500MHz, d₆-DMSO) δ 1.33-1.41 (m, 2H), 1.52-1.69 (br, 1H), 1.83-1.89 (m,2H), 3.23-3.29 (m, 4H), 3.27 (s, 3H), 3.30-3.35 (br, 1H), 3.38-3.44 (m,1H), 4.11 (dt, J=13.5, 4.5 Hz, 2H), 4.55 (d, J=4.5 Hz, 2H), 6.93 (d,J=85.0 Hz, 1H), 8.22 (s, 2H), ¹⁹F NMR (500 MHz, d₆-DMSO) δ 131.8 (s).

EXAMPLE 4a(2E)-3-Fluoro-2-({[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]oxy}methyl)prop-2-en-1-amine4-methylbenzenesulfonate (1:1)

Dissolve(E)-3-fluoro-2-[[2-(4-methoxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]prop-2-en-1-amine(2.316 g, 7.81 mmol) in methyl acetate (3 mL) and stir at 1000 rpm atroom temperature to give a light yellow solution. Add 4-toluenesulfonicacid monohydrate (1.62 g, 8.43 mmol) in a solution of methyl acetate (4mL). The mixture becomes cloudy and a thick yellow slurry quickly forms.Filter the solid by vacuum filtration through filter paper. Rinse thefilter cake with methyl acetate (4 mL) to give a white filter cake. Drythe solid under a vacuum air stream for 10 minutes and then in a vacuumoven at room temperature overnight to give the title compound (3.00 g,81.8%).

X-Ray Powder Diffraction of Example 4a

The X-ray powder diffraction (XRD) pattern of crystalline(2E)-3-fluoro-2-({[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]oxy}methyl)prop-2-en-1-amine4-methylbenzenesulfonate is obtained on a Bruker D4 Endeavor X-raypowder diffractometer, equipped with a CuKα source (λ=1.54060 Å) and aVantec detector, operating at 35 kV and 50 mA. The sample is scannedbetween 4 and 40° in 20, with a step size of 0.009° in 20 and a scanrate of 0.5 seconds/step, and with 0.6 mm divergence, 5.28 fixedanti-scatter, and 9.5 mm detector slits. The dry powder is packed on aquartz sample holder and a smooth surface is obtained using a glassslide. The crystal form diffraction patterns are collected at ambienttemperature and relative humidity. It is well known in thecrystallography art that, for any given crystal form, the relativeintensities of the diffraction peaks may vary due to preferredorientation resulting from factors such as crystal morphology and habit.Where the effects of preferred orientation are present, peak intensitiesare altered, but the characteristic peak positions of the polymorph areunchanged. See, e.g., The United States Pharmacopeia #23, NationalFormulary #18, pages 1843-1844, 1995. Furthermore, it is also well knownin the crystallography art that for any given crystal form the angularpeak positions may vary slightly. For example, peak positions can shiftdue to a variation in the temperature or humidity at which a sample isanalyzed, sample displacement, or the presence or absence of an internalstandard. In the present case, a peak position variability oft 0.2 in 20will take into account these potential variations without hindering theunequivocal identification of the indicated crystal form. Confirmationof a crystal form may be made based on any unique combination ofdistinguishing peaks (in units of ° 2θ), typically the more prominentpeaks. Collect the crystal form diffraction patterns at ambienttemperature and relative humidity and adjust based on NIST 675 standardpeaks at 8.853 and 26.774 degrees 2-theta.

A prepared sample of(2E)-3-fluoro-2-({[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]oxy}methyl)prop-2-en-1-amine4-methylbenzenesulfonate is characterized by an XRD pattern using CuKαradiation as having diffraction peaks (2-theta values) as described inTable 1 below, and in particular having peaks at 18.6 in combinationwith one or more of the peaks selected from 22.4, 19.1, and 21.0; with atolerance for the diffraction angles of +/−0.2° in 2 theta alternativelythe salt can be characterized an XRD pattern having one or more peaks at18.6, 19.1, 21.0, 21.9, and 22.4+/−0.2° in 2 theta, or 17.6, 11.0, 16.8,18.6, 19.1, 21.0, 21.9, 22.4 and 26.1+/−0.2° in 2 theta.

TABLE 1 X-ray powder diffraction peaks of (2E)-3-fluoro-2-({[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]oxy}methyl)prop-2-en-1-amine 4-methylbenzenesulfonate Relative Intensity (% Peak Angle(°2-Theta) +/− 0.2° of most intense peak) 1 7.4 17.6% 2 11.0 23.4% 312.7 5.2% 4 16.8 10.1% 5 18.6 100.0% 6 19.1 42.2% 7 21.0 41.9% 8 21.931.6% 9 22.4 77.5% 10 26.2 18.6%

EXAMPLE 5(E)-3-Fluoro-2-[[2-[(3S)-3-methoxypyrrolidin-1-yl]pyrimidin-5-yl]oxymethyl]prop-2-en-1-amine

Stir a solution of tert-butylN-[(E)-3-fluoro-2-[[2-[(3S)-3-methoxypyrrolidin-1-yl]pyrimidin-5-yl]oxymethyl]allyl]carbamate(481 mg, 1.26 mmol) and trifluoroacetic acid (1 mL, 13.23 mmol) in DCM(3 mL) at room temperature for 1 hour. Concentrate the mixture undervacuum. Subject the residue to prep-HPLC: LC Column: XBridge® C18 30×150mm 5 μm; eluting with 5% 10 mM aqueous NH₄HCO₃ in ACN from 0-2 minutes,then a gradient of 6-11% 10 mM aqueous NH₄HCO₃ in ACN from 2-12 minutes;stop at 18 minutes; column temp: room temperature; flow rate: 35mL/minutes, R_(t)=10.6 minutes; monitor by UV to give the title compound(226 mg, 61.7%) as a white solid with an E:Z ratio greater than 20:1.ES/MS (m/z): 283.1 (M+H), ¹H NMR (500 MHz, CDCl₃) δ 1.12-1.78 (br, 2H),2.07-2.16 (m, 2H), 3.37 (s, 3H), 3.53-3.68 (m, 6H), 4.07 (m, 1H), 4.44(s, 2H), 6.57 (d, J=83.0 Hz, 1H), 8.12 (s, 2H).

EXAMPLE 6(3S)-1-[5-[(E)-2-(Aminomethyl)-3-fluoro-allyloxy]pyrimidin-2-yl]pyrrolidin-3-ol;Dihydrochloride

Dissolve tert-butylN-[(E)-3-fluoro-2-[[2-[(3S)-3-hydroxypyrrolidin-1-yl]pyrimidin-5-yl]oxymethyl]allyl]carbamate(605.9 mg, 1.65 mmol) into a mixture of HCl in MeOH (30 mL, 15 mmol, 0.5mol/L) and HCl in water (5 mL, 60 mmol, 12 mol/L). Stir the resultingclear solution overnight. Concentrate the reaction mixture under vacuumto provide a residue. Subject the residue to pre-HPLC: LC Column:XBridge® C18 30×150 mm 5 μm; H₂O 10 nM N₄HCO₃; at room temperature;eluting with 2% ACN for 0-2 minutes, then a gradient of 2-10% ACN for2-10 minutes, at a flow rate: 35 mL/minutes, R_(t)=8.0 minutes(monitored via UV detection); stopping at 16 mins. Collect theappropriate fractions and concentrate to provide the free base of thetitle compound. Dissolve the free base compound in 0.5 M HCl in MeOH (15mL). Concentrate the solution, add water, and then lyophilize to givethe title product as a light yellow solid with an E:Z ratio greater than20:1 (352.7 mg, 0.982 mmol, 59%). ES/MS (m/z): 269 (M+H), ¹H NMR (500MHz, d₆-DMSO) δ 1.87-1.94 (m, 1H), 1.98-2.05 (m, 1H), 3.44 (d, J=11.5 Hz1H), 3.51-3.61 (m, 5H), 4.39-4.42 (m, 1H), 4.66 (d, J=3.0 Hz, 2H),5.33-5.90 (br, 2H), 7.28 (d, J=82.0 Hz, 1H), 8.35 (s, 2H), 8.35-8.44(br, 3H), ¹⁹F NMR (500 MHz, d₆-DMSO) δ 121.9 (s).

Alternate Preparation of Example 6

Dissolve tert-butylN-[(E)-3-fluoro-2-[[2-[(3S)-3-hydroxypyrrolidin-1-yl]pyrimidin-5-yl]oxymethyl]allyl] carbamate (1.1601 g, 3.15 mmol) in a solution of HCl in EtOAc (50mL, 50 mmol, 1.0 mol/L) (pre-mixed with 0.5 mol/L HCl in MeOH, 5 mL).Stir the resulting solution overnight. Concentrate the white suspensionunder vacuum to provide a white powder. Dissolve the white powder inwater and lyophilize the solution to provide the title compounds as alight yellow solid (860.7 mg, 2.42 mmol, 77%).

The material prepared as Example 6 is dissolved in water (5 mL) andcombined with the material of Alternate Example 6 in water (5 mL).Lyophilize the mixture to give the title compound with an E:Z ratiogreater than 20:1 (1.151 g 3.27 mmol). ES/MS m/z: 269 (M+H), ¹H NMR (500MHz, d₆-DMSO) δ 1.87-1.94 (m, 1H), 1.98-2.05 (m, 1H), 3.44 (d, J=11.5 Hz1H), 3.51-3.61 (m, 5H), 4.39-4.42 (m, 1H), 4.66 (d, J=3.0 Hz, 2H),5.33-5.90 (br, 2H), 7.28 (d, J=82.0 Hz, 1H), 8.35 (s, 2H), 8.35-8.44(br, 3H), ¹⁹F NMR (500 MHz, d₆-DMSO) δ 121.9 (s).

Biological Assays

SSAO/VAP-1 In Vitro Activity

Amine oxidase activity of recombinant SSAO, MAOa, and MAOb isoforms aremeasured using the MAO-Glo™ assay kit from Promega (V1402). Testcompounds (with DMSO as vehicle, 0.5% v/v for SSAO) and the enzyme areincubated for 10 mins at room temperature before the addition of theluminogenic substrate. The substrate concentration is 10 μM for humanrecombinant SSAO. The assays are conducted in a pH 7.4 buffer (50 mMHEPES, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1.4 mM MgCl₂, 0.001% Tween-20)in a well-plate. Oxidation of the substrate is conducted for 2 hrsbefore the addition of detecting reagent according the manufacture'sprotocol. The IC₅₀ value of the tested compounds is calculated byfitting the dose response curve using a 4-parameter non-linearregression routine. The IC₅₀ values for the compounds of Example 3, 5,and 6 are listed in Table 2.

TABLE 2 Ex hSSAO Inhib Rel IC₅₀ (nM) 3 12 ± 1, n = 5 5 32 ± 7, n = 4 652 ± 5, n = 7Data are presented as mean±SEM (SEM=standard error of the mean) for thenumber of assays (n).

The compounds of the Examples exhibited an IC₅₀ for hSSAO of less than60 nM. The compounds of the Examples exhibited an IC₅₀ hMAOa and hMAObmore than 50 μM and 200 μM, respectively, indicating that the compoundsof the Examples are selective for hSSAO over either hMAOa or hMAOb.

SSAO Target Engagement

The SSAO activity in rat plasma and liver tissues are measured using theMAO-Glo™ assay kit from Promega (V1402). The residual SSAO activity inrats after compound treatment is estimated by measuring the total amineoxidase activity in plasma or liver lysates that are insensitive to thepresence of the MAO inhibitor Clogyline and Pargyline. Rats areadministered the compound of Example 2 at the doses of 15, 3, 0.6, 0.12,0.025, 0.005 mg/kg. The control group is administered with the samevolume (2 ml/kg) of the dosing vehicle (hydroxyethyl cellulose 1% w/v,0.25% Tween 80). Plasma and liver at 2 or 24 hours post compoundtreatment are harvested and stored at −78° C. until analysis. Tissuelysates are prepared by homogenization in a lysis buffer (20 mM HEPES,pH 7.4, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100 and 1× RocheComplete protease inhibitor tablet). Tissue particles are removed bycentrifugation at 12,000 rpm at 4° C. for 30 minutes. 40 μl of plasma orliver lysates is incubated with Clogyline (10 μM) and Pargyline (10 μM)for 20 minutes at room temperature before the addition of theluminogenic substrate (50 μM) for 60 minutes. The product generated isquantified according to the manufacture's procedure. The fraction ofactivity that is insensitive to the presence of the MAO inhibitors isused as the surrogate for the residual SSAO activity. The compound ofExample 2 was evaluated in the protocol essentially as described aboveadministered at various doses. The results are listed in Table 3.

TABLE 3 SSAO Target Engagement for Example 2 SSAO Activity (%) DosePlasma Liver (mg/kg) 2 hour 24 hour 24 hour Vehicle 100 ± 7  100 ± 9 100 ± 11  0.005 31 ± 3  70 ± 7 75 ± 18 0.025 21 ± 1  55 ± 9 68 ± 14 0.127 ± 1 35 ± 4 45 ± 8  0.6 4.3 ± 0.8 16.3 ± 2.6 16.2 ± 2.9  3 3.6 ± 1.0 8.8 ± 1.3 7.1 ± 1.7 15 −0.6 ± 0.3   6.6 ± 1.8 9.6 ± 2.6

Data are presented as mean±SEM, n=6

The results indicate that the compound of Example 2 dose-dependentlyinhibits SSAO activity in both rat plasma and liver.

Mouse Model of NASH and Fibrosis Induced by 3H Diet

Male C57BL/6N mice are fed with D09100301 diet (Research Diets, 40% fat,2% cholesterol, 24% fructose, (the, high fat, high cholesterol and highfructose, the “3H diet”) for 150 days. Each mouse is then singly housedafter 5 days for an acclimation period. Plasma alanine aminotransferase(ALT) and cytokeratin 18 (CK18) are measured. After one week ofrecovery, the mice are randomized into 5 groups based on their ALTvalues, CK18 values, and body weight. Animals of each group areadministrated either vehicle (0.5% methylcellulose (MC)+0.25% Tween 80in distilled water) or the compound of Example 6 (at a 0.06, 2, 6, and20 mg/kg dose) once daily in a volume of 5 ml/kg for 11 weeks.

Blood is collected from mice treated with the compound of Example 6 for76 days 2 hours after the last dose. Compound levels in the plasma areanalyzed by mass spectroscopy. The results are listed below in Table 4.Treated mice exhibit a dose-dependent increase in plasma compoundlevels. All groups of mice treated with Example 6 exhibit a significantdecrease in ALT, indicating decreased hepatic lesions in those animals.Animals treated with 6 and 20 mg/kg of the compound of Example 6 alsoexhibit decreased triglyceride levels in blood.

At the completion of the study, the animals are sacrificed and theirlivers excised. Two sections of the left and right lobes are fixed inneutral buffered 10% formalin. Liver tissue slides are stained withhematoxylin and eosin (H&E), Sirius red, and Masson's Trichrome toprepare slides for pathological analysis. All specimens are examinedmicroscopically and scored as a modified Brunt score NASH ActivityScore. Scores are based on the grading scheme and end-points asdescribed in Brunt E. M, et al., “Histopathology of nonalcoholic fattyliver disease,” World J. of Gastroenterol, 2010, 16(42), 5286-5296.Group means are then calculated for each individual end-point. Thefollowing endpoints are used to characterize the fast food model of NASHin mice as modified from NASH endpoints (See Brunt, E. M.“Histopathology of nonalcoholic fatty liver disease,” Clin Liver Dis.,2009, 13, 533-544 and Brunt, E. M, et al., “Nonalcoholicsteatohepatitis: A proposal for grading and staging the histologicallesions”, Am J Gastroenterology, 1999, 94(9), 2467-2474.

Histopathological analysis of the livers from the mice treated with thecompound of Example 6 is provided in Table 4. The results indicate thatthere is a significant decrease in hepatic inflammation, macrovesicularvaculation, and perisinusoidal fibrosis in the mice that are treatedwith 20 mg/kg of the compound of Example 6.

TABLE 4 Efficacy Results for the Compound of Example 6 Plasma Dose Nos.of Compound ALT Plasma TG (mg/kg) Animals Level (ng/ml) (IU/L)¹ (mg/dL)¹Vehicle 12 — 713 ± 43  69 ± 4  0.6 13 66. ± 5  530 ± 45* 55 ± 6  2 13163 ± 21  483 ± 44** 70 ± 11 6 11 560 ± 29 495 ± 25* 46 ± 4* 20 11 2117± 219  466 ± 37*** 45 ± 5* ¹MIXED model is applied to compare foldchanges from baseline adjusted by baseline between compound treatmentgroups and vehicle group, (See “Generalized, Linear, and Mixed Models,”McCulloch, C. E., and Searle, S. R., Eds. John Wiley and Sons, 2000 and“Mixed-Effects Models in S and S-PLUS”, Pinheiro J. C., and Bates, D.M., Eds. Springer, 2000.) Data are presented as mean ± SEM. *p < 0.05;**p < 0.01; ***p < 0.001

TABLE 5 Liver Histopathological Analysis for the Compound of Example 6Score (0-3)¹ Dose Hepatic inflammation Macrovesicular vaculationPerisinusoidal fibrosis (mg/kg) Left Right Left Right Left Right Vehicle2.8 ± 0.1 2.7 ± 0.1 2.8 ± 0.1 2.8 ± 0.1 2.5 ± 0.2 2.3 ± 0.1 0.6 2.6 ±0.1 2.5 ± 0.1 2.5 ± 0.1 2.6 ± 0.1 2.4 ± 0.2 1.9 ± 0.2 2 2.5 ± 0.1 2.6 ±0.1 2.5 ± 0.1 2.7 ± 0.1 2.5 ± 0.2 1.8 ± 0.2 6 2.5 ± 0.2 2.6 ± 0.2 2.9 ±0.1 2.7 ± 0.1 2.6 ± 0.2 2.1 ± 0.3 20  2.1 ± 0.1**  2.1 ± 0.1* 2.4 ± 0.2 2.3 ± 0.1* 1.9 ± 0.2  1.5 ± 0.2* ¹Nonparametric test is applied tocompare scores between compound treatment groups and vehicle group.Scores for left and right laterals are compared separately. Data arepresented as mean ± SEM. *p < 0.05; **p < 0.01; *** p < 0.001

What is claimed is:
 1. A process for preparing a compound of Formula 2:

or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2; andR1 is H or —CH₃, said method comprising the steps of: a) reacting acompound of the formula

wherein n is 1 or 2; and R1 is H or —CH₃, with a compound of the formula

wherein Boc is tert-butoxycarbonyl, to form a compound of the formula

wherein: n is 1 or 2; R1 is H or —CH₃; and Boc is tert-butoxycarbonyl;and b) reacting the compound of the formula

wherein: n is 1 or 2; R1 is H or —CH₃; and Boc is tert-butoxycarbonyl,with an acid to form the compound of Formula 2 or a pharmaceuticallyacceptable salt thereof.
 2. The process of claim 1, wherein the processfurther comprises reacting the pharmaceutically acceptable salt of thecompound of Formula 2 with a base to form the compound of Formula
 2. 3.The process of claim 2, further comprising reacting the compound ofFormula 2 with an acid to form a different pharmaceutically acceptablesalt of the compound of Formula
 2. 4. The process of claim 1, wherein nis
 1. 5. The process of claim 1, wherein n is
 2. 6. The process of claim1, wherein R1 is H.
 7. The process of claim 1, wherein R1 is —CH₃. 8.The process of claim 1, wherein step a) is carried out in the presenceof a base.
 9. The process of claim 8, wherein the base isN,N-diisopropylethylamine or potassium carbonate.
 10. The process ofclaim 1, wherein step a) uses 1,4-dioxane as solvent.
 11. The process ofclaim 1, wherein the acid in step b) is hydrochloric acid ortrifluoroacetic acid.
 12. The process of claim 1, wherein the compoundof the formula

of step a) is prepared by reacting tert-butylN-[(E)-2-(bromomethyl)-3-fluoro-allyl]carbamate with2-chloropyrimidin-5-ol.
 13. The process of claim 12, wherein thereaction is carried out in the presence of potassium carbonate.
 14. Theprocess of claim 12, wherein the reaction uses dimethylformamide assolvent.
 15. The process of claim 1, wherein the compound of Formula 2,or a pharmaceutically acceptable salt thereof, is:(E)-3-fluoro-2-[[2-(4-methoxy-1-piperidyl)pyrimidin-5-yl]oxymethyl]prop-2-en-1-aminedihydrochloride.
 16. The process of claim 1, wherein the compound ofFormula 2, or a pharmaceutically acceptable salt thereof, is:(2E)-3-fluoro-2-({[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]oxy}methyl)prop-2-en-1-amine4-methylbenzenesulfonate.